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1.
Genes (Basel) ; 11(9)2020 08 26.
Article in English | MEDLINE | ID: covidwho-730522

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an RNA virus, is responsible for the coronavirus disease 2019 (COVID-19) pandemic of 2020. Experimental evidence suggests that microRNA can mediate an intracellular defence mechanism against some RNA viruses. The purpose of this study was to identify microRNA with predicted binding sites in the SARS-CoV-2 genome, compare these to their microRNA expression profiles in lung epithelial tissue and make inference towards possible roles for microRNA in mitigating coronavirus infection. We hypothesize that high expression of specific coronavirus-targeting microRNA in lung epithelia may protect against infection and viral propagation, conversely, low expression may confer susceptibility to infection. We have identified 128 human microRNA with potential to target the SARS-CoV-2 genome, most of which have very low expression in lung epithelia. Six of these 128 microRNA are differentially expressed upon in vitro infection of SARS-CoV-2. Additionally, 28 microRNA also target the SARS-CoV genome while 23 microRNA target the MERS-CoV genome. We also found that a number of microRNA are commonly identified in two other studies. Further research into identifying bona fide coronavirus targeting microRNA will be useful in understanding the importance of microRNA as a cellular defence mechanism against pathogenic coronavirus infections.


Subject(s)
Alveolar Epithelial Cells/virology , Betacoronavirus/genetics , MicroRNAs/genetics , Alveolar Epithelial Cells/immunology , Betacoronavirus/pathogenicity , Cell Line, Tumor , Genome, Viral , Humans , MicroRNAs/metabolism , Nucleotide Motifs , Sequence Analysis, RNA
2.
Life Sci Alliance ; 3(9)2020 09.
Article in English | MEDLINE | ID: covidwho-675904

ABSTRACT

The novel emerged SARS-CoV-2 has rapidly spread around the world causing acute infection of the respiratory tract (COVID-19) that can result in severe disease and lethality. For SARS-CoV-2 to enter cells, its surface glycoprotein spike (S) must be cleaved at two different sites by host cell proteases, which therefore represent potential drug targets. In the present study, we show that S can be cleaved by the proprotein convertase furin at the S1/S2 site and the transmembrane serine protease 2 (TMPRSS2) at the S2' site. We demonstrate that TMPRSS2 is essential for activation of SARS-CoV-2 S in Calu-3 human airway epithelial cells through antisense-mediated knockdown of TMPRSS2 expression. Furthermore, SARS-CoV-2 replication was also strongly inhibited by the synthetic furin inhibitor MI-1851 in human airway cells. In contrast, inhibition of endosomal cathepsins by E64d did not affect virus replication. Combining various TMPRSS2 inhibitors with furin inhibitor MI-1851 produced more potent antiviral activity against SARS-CoV-2 than an equimolar amount of any single serine protease inhibitor. Therefore, this approach has considerable therapeutic potential for treatment of COVID-19.


Subject(s)
Alveolar Epithelial Cells/virology , Betacoronavirus/physiology , Furin/genetics , Serine Endopeptidases/genetics , Spike Glycoprotein, Coronavirus/metabolism , Alveolar Epithelial Cells/cytology , Animals , Binding Sites , Cell Line , Chlorocebus aethiops , HEK293 Cells , Humans , Proteolysis , Spike Glycoprotein, Coronavirus/chemistry , Vero Cells , Virus Internalization , Virus Replication
3.
Am J Physiol Lung Cell Mol Physiol ; 319(2): L325-L336, 2020 08 01.
Article in English | MEDLINE | ID: covidwho-636681

ABSTRACT

A dysregulation of the renin-angiotensin system (RAS) has been involved in the genesis of lung injury and acute respiratory distress syndrome from different causes, including several viral infections. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of pneumocytes, the hallmark of the pandemic coronavirus disease 2019 (COVID-19) involving both alveolar interstitium and capillaries, is linked to angiotensin-converting enzyme 2 (ACE2) binding and its functional downregulation. ACE2 is a key enzyme for the balance between the two main arms of the RAS: the ACE/angiotensin (Ang) II/Ang II type 1 receptor axis ("classic RAS") and the ACE2/Ang(1-7)/Mas receptor (MasR) axis ("anti-RAS"). The ACE2 downregulation, as a result of SARS-coronaviruses binding, enhances the classic RAS, leading to lung damage and inflammation with leaky pulmonary blood vessels and fibrosis, when the attenuation mediated by the anti-RAS arm is reduced. ACE inhibitors (ACE-I) and Ang II type 1 receptor blockers (ARB), effective in cardiovascular diseases, were found to prevent and counteract acute lung injury in several experimental models by restoring the balance between these two opposing arms. The evidence of RAS arm disequilibrium in COVID-19 and the hypothesis of a beneficial role of RAS modulation supported by preclinical and clinical studies are the focus of the present review. Preclinical and clinical studies on drugs balancing RAS arms might be the right way to counter COVID-19.


Subject(s)
Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Coronavirus Infections/pathology , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/pathology , Pulmonary Alveoli/pathology , Respiratory Distress Syndrome, Adult/pathology , Alveolar Epithelial Cells/virology , Betacoronavirus/metabolism , Coronavirus Infections/drug therapy , Down-Regulation , Humans , Lung Injury/drug therapy , Lung Injury/prevention & control , Lung Injury/virology , Pandemics , Pneumonia, Viral/drug therapy , Pulmonary Alveoli/blood supply , Pulmonary Alveoli/virology , Receptors, Angiotensin/drug effects , Renin-Angiotensin System/drug effects , Respiratory Distress Syndrome, Adult/virology
4.
EMBO Mol Med ; 12(8): e12642, 2020 08 07.
Article in English | MEDLINE | ID: covidwho-607958

ABSTRACT

A novel coronavirus, SARS-CoV-2, has recently emerged in China and spread internationally, posing a health emergency to the global community. COVID-19 caused by SARS-CoV-2 is associated with an acute respiratory illness that varies from mild to the life-threatening acute respiratory distress syndrome (ARDS). The complement system is part of the innate immune arsenal against pathogens, in which many viruses can evade or employ to mediate cell entry. The immunopathology and acute lung injury orchestrated through the influx of pro-inflammatory macrophages and neutrophils can be directly activated by complement components to prime an overzealous cytokine storm. The manifestations of severe COVID-19 such as the ARDS, sepsis and multiorgan failure have an established relationship with activation of the complement cascade. We have collected evidence from all the current studies we are aware of on SARS-CoV-2 immunopathogenesis and the preceding literature on SARS-CoV-1 and MERS-CoV infection linking severe COVID-19 disease directly with dysfunction of the complement pathways. This information lends support for a therapeutic anti-inflammatory strategy against complement, where a number of clinically ready potential therapeutic agents are available.


Subject(s)
Betacoronavirus , Complement Activation/drug effects , Complement Inactivating Agents/therapeutic use , Coronavirus Infections/drug therapy , Pandemics , Pneumonia, Viral/drug therapy , Adult , Alveolar Epithelial Cells/immunology , Alveolar Epithelial Cells/metabolism , Alveolar Epithelial Cells/virology , Animals , Betacoronavirus/physiology , Child , Complement C3b/antagonists & inhibitors , Complement C3b/physiology , Complement Inactivating Agents/pharmacology , Coronavirus Infections/immunology , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/immunology , Glycosylation , Humans , Immunity, Innate , Ligands , Mice , Models, Animal , Models, Molecular , Pattern Recognition, Automated , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/immunology , Protein Conformation , Protein Processing, Post-Translational , Receptors, Virus/metabolism , Respiratory Distress Syndrome, Adult/etiology , Respiratory Distress Syndrome, Adult/immunology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism
5.
Eur J Pharmacol ; 882: 173288, 2020 Sep 05.
Article in English | MEDLINE | ID: covidwho-599955

ABSTRACT

In December 2019, many pneumonia cases with unidentified sources appeared in Wuhan, Hubei, China, with clinical symptoms like viral pneumonia. Deep sequencing analysis of samples from lower respiratory tract revealed a novel coronavirus, called 2019 novel coronavirus (2019-nCoV). Currently there is a rapid global spread. World Health Organization declare the disease a pandemic condition. The pathologic source of this disease was a new RNA virus from Coronaviridae family, which was named COVID-19. SARS-CoV-2 entry starts with the binding of the spike glycoprotein expressed on the viral envelope to ACE2 on the alveolar surface followed by clathrin-dependent endocytosis of the SARS-CoV-2 and ACE2 complex. SARS-CoV-2 enters the cells through endocytosis process, which is possibly facilitated, via a pH dependent endosomal cysteine protease cathepsins. Once inside the cells, SARS-CoV-2 exploits the endogenous transcriptional machinery of alveolar cells to replicate and spread through the entire lung. Endosomal acidic pH for SARS-CoV-2 processing and internalization is critical. After entering the cells, it possibly activates or hijack many intracellular pathways in favor of its replication. In the current opinion article, we will explain the possible involvement of unfolded protein response as a cellular stress response to the SARS-CoV-2 infection.


Subject(s)
Alveolar Epithelial Cells/drug effects , Coronavirus Infections/drug therapy , Endoplasmic Reticulum/drug effects , Ionophores/pharmacology , Pneumonia, Viral/drug therapy , Alveolar Epithelial Cells/cytology , Alveolar Epithelial Cells/metabolism , Alveolar Epithelial Cells/virology , Betacoronavirus/metabolism , Clathrin-Coated Vesicles/drug effects , Clathrin-Coated Vesicles/metabolism , Coronavirus Infections/virology , Endocytosis/drug effects , Endoplasmic Reticulum/metabolism , Endosomes/drug effects , Endosomes/metabolism , Humans , Ionophores/therapeutic use , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/virology , Unfolded Protein Response/drug effects
6.
Am J Physiol Lung Cell Mol Physiol ; 319(1): L115-L120, 2020 07 01.
Article in English | MEDLINE | ID: covidwho-558506

ABSTRACT

COVID-19 can be divided into three clinical stages, and one can speculate that these stages correlate with where the infection resides. For the asymptomatic phase, the infection mostly resides in the nose, where it elicits a minimal innate immune response. For the mildly symptomatic phase, the infection is mostly in the pseudostratified epithelium of the larger airways and is accompanied by a more vigorous innate immune response. In the conducting airways, the epithelium can recover from the infection, because the keratin 5 basal cells are spared and they are the progenitor cells for the bronchial epithelium. There may be more severe disease in the bronchioles, where the club cells are likely infected. The devastating third phase is in the gas exchange units of the lung, where ACE2-expressing alveolar type II cells and perhaps type I cells are infected. The loss of type II cells results in respiratory insufficiency due to the loss of pulmonary surfactant, alveolar flooding, and possible loss of normal repair, since type II cells are the progenitors of type I cells. The loss of type I and type II cells will also block normal active resorption of alveolar fluid. Subsequent endothelial damage leads to transudation of plasma proteins, formation of hyaline membranes, and an inflammatory exudate, characteristic of ARDS. Repair might be normal, but if the type II cells are severely damaged alternative pathways for epithelial repair may be activated, which would result in some residual lung disease.


Subject(s)
Alveolar Epithelial Cells/virology , Betacoronavirus/pathogenicity , Coronavirus Infections/virology , Epithelial Cells/virology , Pneumonia, Viral/virology , Alveolar Epithelial Cells/metabolism , Coronavirus Infections/diagnosis , Coronavirus Infections/therapy , Epithelial Cells/metabolism , Epithelium/metabolism , Epithelium/virology , Humans , Lung/metabolism , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/therapy , Respiratory Mucosa/metabolism , Respiratory Mucosa/virology
8.
Emerg Infect Dis ; 26(9)2020 09.
Article in English | MEDLINE | ID: covidwho-274292

ABSTRACT

An autopsy of a patient in Japan with coronavirus disease indicated pneumonia lung pathology, manifested as diffuse alveolar damage. We detected severe acute respiratory syndrome coronavirus 2 antigen in alveolar epithelial cells and macrophages. Coronavirus disease is essentially a lower respiratory tract disease characterized by direct viral injury of alveolar epithelial cells.


Subject(s)
Betacoronavirus , Coronavirus Infections/pathology , Pneumonia, Viral/pathology , Aged, 80 and over , Alveolar Epithelial Cells/pathology , Alveolar Epithelial Cells/virology , Autopsy , Coronavirus Infections/virology , Female , Humans , Immunohistochemistry , Japan , Lung/pathology , Lung/virology , Pandemics , Pneumonia, Viral/virology
9.
Nature ; 583(7818): 834-838, 2020 07.
Article in English | MEDLINE | ID: covidwho-261141

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus with high nucleotide identity to SARS-CoV and to SARS-related coronaviruses that have been detected in horseshoe bats, has spread across the world and had a global effect on healthcare systems and economies1,2. A suitable small animal model is needed to support the development of vaccines and therapies. Here we report the pathogenesis and transmissibility of SARS-CoV-2 in golden (Syrian) hamsters (Mesocricetus auratus). Immunohistochemistry assay demonstrated the presence of viral antigens in nasal mucosa, bronchial epithelial cells and areas of lung consolidation on days 2 and 5 after inoculation with SARS-CoV-2, followed by rapid viral clearance and pneumocyte hyperplasia at 7 days after inoculation. We also found viral antigens in epithelial cells of the duodenum, and detected viral RNA in faeces. Notably, SARS-CoV-2 was transmitted efficiently from inoculated hamsters to naive hamsters by direct contact and via aerosols. Transmission via fomites in soiled cages was not as efficient. Although viral RNA was continuously detected in the nasal washes of inoculated hamsters for 14 days, the communicable period was short and correlated with the detection of infectious virus but not viral RNA. Inoculated and naturally infected hamsters showed apparent weight loss on days 6-7 post-inoculation or post-contact; all hamsters returned to their original weight within 14 days and developed neutralizing antibodies. Our results suggest that features associated with SARS-CoV-2 infection in golden hamsters resemble those found in humans with mild SARS-CoV-2 infections.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/transmission , Coronavirus Infections/virology , Disease Models, Animal , Lung/pathology , Lung/virology , Mesocricetus/virology , Pneumonia, Viral/transmission , Pneumonia, Viral/virology , Aerosols , Alveolar Epithelial Cells/pathology , Alveolar Epithelial Cells/virology , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Antigens, Viral/immunology , Antigens, Viral/isolation & purification , Antigens, Viral/metabolism , Betacoronavirus/immunology , Betacoronavirus/isolation & purification , Betacoronavirus/metabolism , Bronchi/pathology , Bronchi/virology , Coronavirus Infections/immunology , Duodenum/virology , Fomites/virology , Housing, Animal , Kidney/virology , Male , Mesocricetus/immunology , Nasal Mucosa/virology , Pandemics , Pneumonia, Viral/immunology , RNA, Viral/analysis , Viral Load , Weight Loss
11.
Antioxid Redox Signal ; 33(2): 59-65, 2020 07 10.
Article in English | MEDLINE | ID: covidwho-108750

ABSTRACT

Human lungs single-cell RNA sequencing data from healthy donors (elderly and young; GEO accession no. GSE122960) were analyzed to isolate and specifically study gene expression in alveolar type II cells. Colocalization of angiotensin-converting enzyme 2 (ACE2) and TMPRSS2 enables severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2) to enter the cells. Expression levels of these genes in the alveolar type II cells of elderly and young patients were comparable and, therefore, do not seem to be responsible for worse outcomes observed in coronavirus disease 2019 (COVID-19) affected elderly. In cells from the elderly, 263 genes were downregulated and 95 upregulated. Superoxide dismutase 3 (SOD3) was identified as the top-ranked gene that was most downregulated in the elderly. Other redox-active genes that were also downregulated in cells from the elderly included activating transcription factor 4 (ATF4) and metallothionein 2A (M2TA). ATF4 is an endoplasmic reticulum stress sensor that defends lungs via induction of heme oxygenase 1. The study of downstream factors known to be induced by ATF4, according to Ingenuity Pathway Analysis™, identified 24 candidates. Twenty-one of these were significantly downregulated in the cells from the elderly. These downregulated candidates were subjected to enrichment using the Reactome Database identifying that in the elderly, the ability to respond to heme deficiency and the ATF4-dependent ability to respond to endoplasmic reticulum stress is significantly compromised. SOD3-based therapeutic strategies have provided beneficial results in treating lung disorders including fibrosis. The findings of this study propose the hypotheses that lung-specific delivery of SOD3/ATF4-related antioxidants will work in synergy with promising antiviral drugs such as remdesivir to further improve COVID-19 outcomes in the elderly.


Subject(s)
Activating Transcription Factor 4/genetics , Coronavirus Infections/genetics , Lung/metabolism , Pneumonia, Viral/genetics , Superoxide Dismutase/genetics , Adult , Aged , Alveolar Epithelial Cells/pathology , Alveolar Epithelial Cells/virology , Antioxidants/therapeutic use , Betacoronavirus/pathogenicity , Coronavirus Infections/therapy , Coronavirus Infections/virology , Female , Gene Expression Regulation/genetics , Heme Oxygenase-1/genetics , Humans , Lung/pathology , Lung/virology , Male , Metallothionein/genetics , Middle Aged , Pandemics , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/therapy , Pneumonia, Viral/virology , Serine Endopeptidases/genetics
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